UVB radiation is a complete carcinogen for skin and initiates signaling pathways and mutations that promote the formation of precancerous actinic keratoses (AKs) and cutaneous squamous cell carcinomas (cSCCs). Both AKs and cSCCs are very common in older individuals with a history of sun-exposure, and the incidence of these lesions is expected to rise in the future. Common mutations in human cSCCs include loss-of-function mutations in p53 and gain-of-function mutations in Ras. In human AKs and cSCCs, Src-family tyrosine kinases (SFKs) are activated in lesional cells compared with non- lesional epidermis, suggesting that SFKs promote skin cancer; this is consistent with the observation that the SFK Fyn is an effector of oncogenic Ras in human keratinocytes. Analysis of human cSCCs and AKs consistently shows decreased Srcasm levels suggesting that Srcasm downregulation may be necessary for neoplasia. Our previous data show that Fyn downregulates p53 and induces the spontaneous formation of precancerous lesions and cSCCs in K14-Fyn Y528F transgenic mice. These precancerous lesions and cSCCs resemble their human counterparts at the histologic and molecular levels. Raising Srcasm levels in these mice normalizes Fyn kinase activity, restores p53, and inhibits tumor formation. We genetically deleted Srcasm in mice and these mice have markedly reduced p53 levels in skin. Recent data show that UVB-treatment of Srcasm null mice produces precancerous lesions that resemble human AKs in 5 weeks. Together, these data show that Fyn and Srcasm form a signaling nexus that regulates skin cancer. The primary goal of this proposal is to demonstrate that Fyn and Srcasm play important Fyn in murine models and in genetically engineered, reconstituted human skin. Promoting Fyn activity should enhance UVB-induced signaling and DNA damage while increasing Srcasm levels should inhibit UVB-induced DNA damage and skin cancer. Decreasing Fyn should inhibit Ras-induced skin cancer. In these studies, we will show how Fyn and Srcasm regulate signaling pathways that contribute to skin cancer. Targeting the kinases responsible for promoting neoplasia in these mouse models with topically applied small molecule kinase inhibitors results in regression of these tumors, suggesting that such molecules may have potential in treating human lesions. The data obtained through this research proposal will further our knowledge of how SFKs and Srcasm regulate UVB-induced DNA damage and skin carcinogenesis. This work will also provide new candidate molecules that may improve topical therapies to treat AKs and cSCCs in patients.